HIGHLIGHTS OF PRESCRIBING INFORMATION … mutations as detected by an FDA-approved ... Hemorrhage: ... Review the Full Prescribing Information for dabrafenib for information on the

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

MEKINIST safely and effectively. See full prescribing information for

MEKINIST.

MEKINIST® (trametinib) tablets, for oral use

Initial U.S. Approval: 2013

------------------------------RECENT MAJOR CHANGES------------------------

Indications and Usage (1.1-1.3) 4/2018

Indications and Usage (1.4, 1.5) 5/2018

Dosage and Administration (2.2, 2.3, 2.4) 4/2018

Dosage and Administration (2.1, 2.5, 2.6, 2.7) 5/2018

Warnings and Precautions (5) 4/2018

------------------------------INDICATIONS AND USAGE-------------------------

MEKINIST is a kinase inhibitor indicated as a single agent for the treatment

of patients with unresectable or metastatic melanoma with BRAF V600E or

V600K mutations as detected by an FDA-approved test. (1.1, 2.1)

MEKINIST is indicated, in combination with dabrafenib, for:

the treatment of patients with unresectable or metastatic melanoma with

BRAF V600E or V600K mutations as detected by an FDA-approved

test. (1.1, 2.1) the adjuvant treatment of patients with melanoma with BRAF V600E or

V600K mutations, as detected by an FDA-approved test, and

involvement of lymph node(s), following complete resection. (1.2, 2.1)

the treatment of patients with metastatic non-small cell lung cancer

(NSCLC) with BRAF V600E mutation as detected by an FDA-approved

test. (1.3, 2.1)

the treatment of patients with locally advanced or metastatic anaplastic

thyroid cancer (ATC) with BRAF V600E mutation and with no

satisfactory locoregional treatment options (1.4, 2.1)

Limitations of Use: MEKINIST is not indicated for treatment of patients with

melanoma who have progressed on prior BRAF-inhibitor therapy. (1.5)

-------------------------DOSAGE AND ADMINISTRATION---------------------

The recommended dosage regimen of MEKINIST is 2 mg orally once

daily. Take MEKINIST at least 1 hour before or at least 2 hours after a

meal. (2)

------------------------DOSAGE FORMS AND STRENGTHS-------------------

Tablets: 0.5 mg and 2 mg (3)

-----------------------------------CONTRAINDICATIONS--------------------------

None (4)

----------------------------WARNINGS AND PRECAUTIONS-------------------

New Primary Malignancies, Cutaneous and Non-cutaneous, can occur

when MEKINIST is used with dabrafenib. Monitor patients for new

malignancies prior to initiation of therapy, while on therapy, and

following discontinuation of treatment. (5.1)

Hemorrhage: Major hemorrhagic events can occur. Monitor for signs

and symptoms of bleeding (5.2)

Colitis and Gastrointestinal Perforation: Colitis and gastrointestinal

perforation can occur in patients receiving MEKINIST. (5.3)

Venous Thromboembolism: Deep vein thrombosis and pulmonary

embolism can occur in patients receiving MEKINIST. (5.4, 2.7)

Cardiomyopathy: Assess LVEF before treatment, after one month of

treatment, then every 2 to 3 months thereafter. (5.5, 2.7)

Ocular Toxicities: Perform ophthalmologic evaluation for any visual

disturbances. For Retinal Vein Occlusion (RVO), permanently

discontinue MEKINIST. (5.6, 2.7)

Interstitial Lung disease (ILD): Withhold MEKINIST for new or

progressive unexplained pulmonary symptoms. Permanently discontinue

MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.7)

Serious Febrile Reactions: Can occur when MEKINIST is used with

dabrafenib. (5.8, 2.7)

Serious Skin Toxicity: Monitor for skin toxicities and for secondary

infections. Discontinue MEKINIST for intolerable Grade 2, or Grade 3

or 4 rash not improving within 3 weeks despite interruption of

MEKINIST. (5.9, 2.7)

Hyperglycemia: Monitor serum glucose levels in patients with pre-

existing diabetes or hyperglycemia. (5.10)

Risks Associated with Combination Treatment: Review the Full

Prescribing Information for dabrafenib for information on the serious

risks of dabrafenib prior to initiation of MEKINIST in combination with

dabrafenib. (5.11)

Embryo-Fetal toxicity: MEKINIST can cause fetal harm. Advise

females of reproductive potential of potential risk to a fetus and to use

effective contraception. (5.12, 8.1, 8.3)

---------------------------------ADVERSE REACTIONS----------------------------

Most common adverse reactions (≥ 20%) for MEKINIST as a single agent

include rash, diarrhea, and lymphedema. (6.1)

Most common adverse reactions (≥ 20%) for MEKINIST with dabrafenib

include:

Unresectable or metastatic melanoma: pyrexia, nausea, rash, chills,

diarrhea, vomiting, hypertension, and peripheral edema. (6.1)

Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache,

rash, chills, diarrhea, vomiting, arthralgia, and myalgia. (6.1)

NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin,

decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Novartis

Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch.

----------------------------USE IN SPECIFIC POPULATIONS-------------------

Lactation: Do not breast feed. (8.2)

Females and Males of Reproductive Potential: May impair fertility.

Counsel patients on pregnancy planning and prevention. (8.3)

See 17 for PATIENT COUNSELING INFORMATION and FDA-

approved patient labeling.

Revised: 5/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 1.1 BRAF V600E or V600K Mutation-Positive Unresectable or

Metastatic Melanoma 1.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-

Positive Melanoma 1.3 BRAF V600E Mutation-Positive Metastatic NSCLC 1.4 BRAF V600E Mutation-Positive Locally Advanced or

Metastatic Anaplastic Thyroid Cancer 1.5 Limitations of Use

2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage for Unresectable or Metastatic

Melanoma 2.3 Recommended Dosage for the Adjuvant Treatment of

Melanoma 2.4 Recommended Dosage for NSCLC 2.5 Recommended Dosage for ATC 2.6 Administration 2.7 Dosage Modifications for Adverse Reactions

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 New Primary Malignancies 5.2 Hemorrhage

5.3 Colitis and Gastrointestinal Perforation 5.4 Venous Thromboembolism 5.5 Cardiomyopathy 5.6 Ocular Toxicities 5.7 Interstitial Lung Disease 5.8 Serious Febrile Reactions 5.9 Serious Skin Toxicity 5.10 Hyperglycemia 5.11 Risks Associated with Combination Treatment 5.12 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience

7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 12.2 Pharmacodynamics

http://www.fda.gov/medwatch

2

12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES

14.1 BRAF V600E or V600K Mutation-Positive Unresectable or

Metastatic Melanoma 14.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-

Positive Melanoma 14.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell

Lung Cancer (NSCLC)

14.4 BRAF V600E Mutation-Positive Locally Advanced or

Metastatic Anaplastic Thyroid Cancer (ATC) 14.5 Lack of Clinical Activity in Metastatic Melanoma

Following BRAF-Inhibitor Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not

listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

MEKINIST® is indicated, as a single agent or in combination with dabrafenib, for the treatment of patients with

unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved

test [see Dosage and Administration (2.1), (2.2)].

1.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

MEKINIST is indicated, in combination with dabrafenib, for the adjuvant treatment of patients with melanoma

with BRAF V600E or V600K mutations as detected by an FDA-approved test, and involvement of lymph

node(s), following complete resection [see Dosage and Administration (2.1), (2.3)].

1.3 BRAF V600E Mutation-Positive Metastatic NSCLC

MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with metastatic non-small

cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and

Administration (2.1), (2.4)].

1.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer

MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with locally advanced or

metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional

treatment options [see Dosage and Administration (2.1), (2.5)].

1.5 Limitations of Use

MEKINIST is not indicated for treatment of patients with melanoma who have progressed on prior BRAF-

inhibitor therapy [see Clinical Studies (14.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Melanoma

Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of

treatment with MEKINIST and dabrafenib [see Clinical Studies (14.1), (14.2)].

Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at:

http://www.fda.gov/CompanionDiagnostics.

NSCLC

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with

MEKINIST and dabrafenib [see Clinical Studies (14.3)].

Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at:

http://www.fda.gov/CompanionDiagnostics.

ATC

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with

MEKINIST and dabrafenib [see Clinical Studies (14.4)].

2.2 Recommended Dosage for Unresectable or Metastatic Melanoma

The recommended dosage of MEKINIST is 2 mg orally taken once daily, as a single agent or in combination

with dabrafenib, until disease progression or unacceptable toxicity. Refer to the dabrafenib prescribing

information for recommended dabrafenib dosing information.

http://www.fda.gov/CompanionDiagnostics

http://www.fda.gov/CompanionDiagnostics

2.3 Recommended Dosage for the Adjuvant Treatment of Melanoma

The recommended dosage of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until

disease recurrence or unacceptable toxicity for up to 1 year. Refer to the dabrafenib prescribing information for

recommended dabrafenib dosing information.

2.4 Recommended Dosage for NSCLC

The recommended dose of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until

disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended

dabrafenib dosing information.

2.5 Recommended Dosage for ATC

The recommended dose of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until

disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended

dabrafenib dosing information.

2.6 Administration

• Take MEKINIST doses approximately 24 hours apart.

• Take MEKINIST at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)].

• Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST.

2.7 Dosage Modifications for Adverse Reactions

Dose reductions for adverse reactions associated with MEKINIST are presented in Table 1.

Table 1. Recommended Dose Reductions for MEKINIST for Adverse Reactions

Action Recommended Dose

First Dose Reduction 1.5 mg orally once daily

Second Dose Reduction 1 mg orally once daily

Subsequent Modification Permanently discontinue if unable to tolerate MEKINIST

1 mg orally once daily

Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 2.

Table 2. Recommended Dosage Modifications for MEKINIST for Adverse Reactions

Severity of Adverse Reactiona MEKINISTb

Venous Thromboembolism

Uncomplicated DVT or PE Withhold MEKINIST for up to 3 weeks.

If improved to Grade 0-1, resume at a lower dose level.

If not improved, permanently discontinue.

Life threatening PE Permanently discontinue MEKINIST.

Cardiac

Asymptomatic, absolute decrease in left ventricular

ejection fraction (LVEF) of 10% or greater from

baseline and is below institutional lower limits of

normal (LLN) from pretreatment value

Withhold MEKINIST for up to 4 weeks.

If improved to normal LVEF value, resume at a lower

dose level.

If not improved to normal LVEF value, permanently

discontinue.

Symptomatic congestive heart failure

Absolute decrease in LVEF of greater than 20% from

baseline that is below LLN

Permanently discontinue MEKINIST.

Ocular Toxicities

Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks.

If improved, resume MEKINIST at same or lower dose

level.

If not improved, discontinue or resume at a lower dose.

Retinal vein occlusion

Permanently discontinue MEKINIST.

Pulmonary

Interstitial lung disease/pneumonitis Permanently discontinue MEKINIST.

Febrile Drug Reaction

Fever higher than 104°F

Fever complicated by rigors, hypotension, dehydration,

or renal failure

Withhold MEKINIST until fever resolves. Then resume

MEKINIST at same or lower dose level.

Dermatologic

Intolerable Grade 2

Grade 3 or 4

Withhold MEKINIST for up to 3 weeks.

If improved, resume at a lower dose level.


Other Adverse Reactionsc

Intolerable Grade 2

Any Grade 3

Withhold MEKINIST

If improved to Grade 0-1, resume at a lower dose level.


First occurrence of any Grade 4 Withhold MEKINIST until adverse reaction improves to

Grade 0-1. Then resume at a lower dose level.

Or

Permanently discontinue.

Recurrent Grade 4 Permanently discontinue MEKINIST. a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Table 1 for recommended dose reductions of MEKINIST. c Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions

of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary

cutaneous malignancies.

Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with

dabrafenib.

3 DOSAGE FORMS AND STRENGTHS

0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’

on the opposing face.

2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the

opposing face.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 New Primary Malignancies

Cutaneous Malignancies

In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell

carcinoma in patients receiving MEKINIST and dabrafenib was 3.3%. Among the 7 patients receiving

MEKINIST with dabrafenib who developed basal cell carcinoma, 2 experienced more than one occurrence

(range: 1 to 3). Cutaneous squamous cell carcinomas and keratoacanthoma (cuSCC) and new primary

melanoma occurred in 3% and 0.5% of patients receiving MEKINIST and dabrafenib, respectively.

In the COMBI-AD study in the adjuvant treatment of melanoma, cuSCC and new primary melanoma occurred

in 1% and < 1% of patients receiving MEKINIST plus dabrafenib, respectively.

In Study BRF113928 in patients with NSCLC, cuSCC occurred in 3.2% of patients receiving MEKINIST plus

dabrafenib.

Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months

while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications

of MEKINIST are recommended in patients who develop new primary cutaneous malignancies.

Non-Cutaneous Malignancies

Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with

activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for

dabrafenib]. In the COMBI-d, COMBI-AD, and BRF113928 studies, non-cutaneous malignancies occurred in

1.4%, 1%, and 1.1% of patients receiving MEKINIST plus dabrafenib, respectively.

Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous

malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous

malignancies.

5.2 Hemorrhage

Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can

occur with MEKINIST.

In the COMBI-d study, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib

was 19%. Gastrointestinal hemorrhage occurred in 6% of patients receiving MEKINIST in combination with

dabrafenib. In the COMBI-d study, 1.4% of patients receiving MEKINIST and dabrafenib developed fatal

intracranial hemorrhage. No fatal hemorrhagic events were observed in the COMBI-AD study. In Study

BRF113928, fatal hemorrhagic events occurred in 2.2% of patients receiving MEKINIST with dabrafenib; these

events were retroperitoneal hemorrhage and subarachnoid hemorrhage.

Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic

events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the

next lower dose level.

5.3 Colitis and Gastrointestinal Perforation

Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking

MEKINIST as a single-agent and when administered with dabrafenib. Across clinical trials of MEKINIST,

colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients.

Monitor patients closely for colitis and gastrointestinal perforations.

5.4 Venous Thromboembolism

In the COMBI-d study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of

patients receiving MEKINIST and dabrafenib. In the COMBI-AD study, DVT and PE occurred in 2% of

patients receiving MEKINIST and dabrafenib. In Study BRF113928, DVT and PE occurred in 4.3% of patients

receiving MEKINIST and dabrafenib.

Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of

breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life threatening PE.

Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be

resumed at a lower dose level [see Dosage and Administration (2.7)].

5.5 Cardiomyopathy

Cardiomyopathy, including cardiac failure, can occur with MEKINIST.

In the METRIC study in patients with unresectable or metastatic melanoma, cardiomyopathy [defined as

cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in

7% of patients receiving MEKINIST; no chemotherapy-treated patient developed cardiomyopathy. Four percent

of patients required discontinuation and/or dose reduction of MEKINIST. Cardiomyopathy resolved in 10 of 14

patients.

Across clinical trials of MEKINIST as a single agent, 11% of patients developed evidence of cardiomyopathy

[decrease in LVEF below institutional lower limits of normal (LLN) with an absolute decrease in LVEF ≥ 10%

below baseline] and 5% demonstrated a decrease in LVEF below institutional LLN with an absolute decrease in

LVEF of ≥ 20% below baseline.

In the COMBI-d study, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an

absolute decrease in LVEF ≥ 10% below baseline) occurred in 6% of patients receiving MEKINIST and

dabrafenib and resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation

(1.5%) of MEKINIST. Cardiomyopathy resolved in 10 of 12 patients receiving MEKINIST and dabrafenib.

In the COMBI-AD study, cardiomyopathy, defined as a decrease in LVEF below the institutional lower limit of

normal with an absolute decrease in LVEF > 10% below screening, occurred in 3% of patients receiving

MEKINIST with dabrafenib and resulted in discontinuation, dose reduction, and dose interruption of drug in

0.2%, 1.6%, and 2.1% of patients, respectively. Cardiomyopathy resolved in 12 of 14 patients receiving

MEKINIST with dabrafenib.

In Study BRF113298, cardiomyopathy, defined as a decrease in LVEF below the institutional lower limit of

normal with an absolute decrease in LVEF > 10% below baseline, occurred in 9% of patients receiving

MEKINIST with dabrafenib and resulted in dose interruption and permanent discontinuation of MEKINIST in

5% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving MEKINIST and

dabrafenib.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a

single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on

treatment. Withhold MEKINIST for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment

values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic

LV dysfunction of > 20% from baseline that is below LLN that does not resolve within 4 weeks, permanently

discontinue MEKINIST [see Dosage and Administration (2.7)].

5.6 Ocular Toxicities

Retinal Vein Occlusion (RVO)

Across clinical trials with MEKINIST, the incidence of RVO was 0.2%. RVO may lead to macular edema,

decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other

visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO [see Dosage and

Administration (2.7)].

Retinal Pigment Epithelial Detachment (RPED)

Retinal pigment epithelial detachment (RPED) can occur with MEKINIST administration. Retinal detachments

may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina.

In melanoma and NSCLC trials, routine monitoring of patients to detect asymptomatic RPED was not

conducted; therefore, the true incidence of this finding is unknown.

Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances.

Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat

ophthalmological evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST

if no improvement after 3 weeks [see Dosage and Administration (2.7)].

5.7 Interstitial Lung Disease

In clinical trials of single-agent MEKINIST, ILD or pneumonitis occurred in 2% of patients. In the METRIC

study, 2.4% of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required

hospitalization. In the COMBI-d, COMBI-AD, and BRF113928 studies, 1.0%, < 1%, and 2.2% of patients

receiving MEKINIST and dabrafenib developed pneumonitis, respectively.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings

including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently

discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis [see Dosage and


5.8 Serious Febrile Reactions

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or

renal failure, can occur when MEKINIST is administered with dabrafenib.

Fever (serious and non-serious) occurred in 57% of patients with unresectable or metastatic melanoma receiving

MEKINIST and dabrafenib. Approximately one-half of the patients who received MEKINIST and dabrafenib

and experienced pyrexia had three or more discrete episodes.

Across clinical trials of MEKINIST administered with dabrafenib in patients with unresectable or metastatic

melanoma, serious febrile reactions or fever of any severity complicated by severe rigors/chills, hypotension,

dehydration, renal failure, or syncope, occurred in 17% of patients receiving MEKINIST and dabrafenib. Fever

was complicated by severe chills/rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in

0.7% of patients.

Withhold MEKINIST for fever higher than 104ºF or for serious febrile reactions or fever accompanied by

hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection.

Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to

Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.7)].

Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of

severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone

10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline

within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension

renal failure, or severe chills/rigors, and there is no evidence of active infection.

5.9 Serious Skin Toxicity

In the METRIC study, the overall incidence of any skin toxicity, the most common of which were rash,

dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients

receiving MEKINIST. Severe skin toxicity occurred in 12% of patients treated with MEKINIST. Skin toxicity

requiring hospitalization occurred in 6% of patients treated with MEKINIST, most commonly for secondary

infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection.

Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was

required in 1% of patients with skin toxicity.

In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving MEKINIST

and dabrafenib. No serious or severe cases of skin toxicity occurred in patients treated with MEKINIST and

dabrafenib. Reductions in the dose of MEKINIST were required in 5% of patients receiving MEKINIST and

dabrafenib and no patients required permanent discontinuation of MEKINIST for skin toxicity.

Across clinical trials of MEKINIST administered with dabrafenib in patients with unresectable or metastatic

melanoma, serious skin toxicity occurred in 0.7% of patients.

Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients

with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.7)].

5.10 Hyperglycemia

In the COMBI-d study, 27% of patients with a history of diabetes who received MEKINIST and dabrafenib

required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values

occurred in 5% and 0.5% of patients receiving MEKINIST and dabrafenib, respectively.

Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered

with dabrafenib in patients with pre-existing diabetes or hyperglycemia.

5.11 Risks Associated with Combination Treatment

MEKINIST is indicated for use in combination with dabrafenib. Review the Full Prescribing Information for

dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib.

5.12 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when

administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater

than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended

clinical dose. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking

MEKINIST, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use effective contraception during treatment with

MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they

become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations

(8.1)].

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

New Primary Malignancies [see Warnings and Precautions (5.1)]

Hemorrhage [see Warnings and Precautions (5.2)]

Colitis and Gastrointestinal Perforation [see Warnings and Precautions (5.3)]

Venous Thromboembolism [see Warnings and Precautions (5.4)]

Cardiomyopathy [see Warnings and Precautions (5.5)]

Ocular Toxicities [see Warnings and Precautions (5.6)]

Interstitial Lung Disease [see Warnings and Precautions (5.7)]

Serious Febrile Reactions [see Warnings and Precautions (5.8)]

Serious Skin Toxicity [see Warnings and Precautions (5.9)]

Hyperglycemia [see Warnings and Precautions (5.10)]

There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing

information for additional information.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice.

The data described in the Warnings and Precautions section reflect exposure to MEKINIST administered as a

single agent in 329 patients with various solid tumors and exposure to MEKINIST administered with dabrafenib

in 559 patients with unresectable or metastatic melanoma and 93 patients with NSCLC. MEKINIST as a single

agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30

(9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label,

single-arm trials (N = 118) and in an open-label, randomized, active-controlled trial (N = 211; the METRIC

study). The median age was 54 years, 60% were male, > 99% were White, and all patients had unresectable or

metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST.

Unresectable or Metastatic BRAF V600E or V600K Mutation Positive Melanoma

MEKINIST Administered as a Single Agent

Table 3 presents adverse reactions identified from analyses of the METRIC study, a randomized, open-label

trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma receiving

MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every

3 weeks or paclitaxel 175 mg/m2 every 3 weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF,

history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart

failure (New York Heart Association) were excluded. The median duration of treatment with MEKINIST was

4.3 months. In this study, 9% of patients receiving MEKINIST experienced adverse reactions resulting in

permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent

discontinuation of MEKINIST were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal

failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST.

Rash and decreased LVEF were the most common reasons cited for dose reductions of MEKINIST.

Table 3. Selected Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKINIST in the

METRIC Study and at a Higher Incidence (≥ 5%) than in the Chemotherapy Arm or ≥ 2% (Grades 3 or

4) Adverse Reactions

Adverse Reactions

MEKINIST Chemotherapy

N = 211 N = 99

All

Gradesa

Grades

3 and 4b

All

Gradesa

Grades

3 and 4b

Skin and subcutaneous tissue

Rash 57 8 10 0

Acneiform dermatitis 19 < 1 1 0

Dry skin 11 0 0 0

Pruritus 10 2 1 0

Paronychia 10 0 1 0

Gastrointestinal

Diarrhea 43 0 16 2

Stomatitisc 15 2 2 0

Abdominal paind 13 1 5 1

Vascular

Lymphedemae 32 1 4 0

Hypertension 15 12 7 3

Hemorrhagef 13 < 1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. e Includes lymphedema, edema, and peripheral edema. f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage,

hematuria, and conjunctival hemorrhage.

Other clinically important adverse reactions observed in less than or equal to 10% of patients (N = 329) treated

with MEKINIST were:

Cardiac Disorders: Bradycardia

Gastrointestinal Disorders: Dry mouth

Infections and Infestations: Folliculitis, rash pustular, cellulitis

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis

Nervous System Disorders: Dizziness, dysgeusia

Ocular Disorders: Blurred vision, dry eye

Table 4. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Treated with

MEKINIST in the METRIC Study [Between-arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or

4)a]

Test

MEKINIST Chemotherapy

N = 211 N = 99

All

Grades

Grades

3 and 4

All

Grades

Grades

3 and 4

Increased aspartate aminotransferase (AST) 60 2 16 1

Hypoalbuminemia 42 2 23 1

Increased alanine aminotransferase (ALT) 39 3 20 3

Anemia 38 2 26 3

Increased alkaline phosphatase 24 2 18 3 a No Grade 4 events were reported in either treatment arm.

MEKINIST Administered with Dabrafenib

The safety of MEKINIST, administered with dabrafenib, was evaluated in 559 patients with previously

untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received MEKINIST in

two trials, the COMBI-d study (n = 209), a multicenter, double-blind, randomized (1:1), active-controlled trial

and the COMBI-v study (n = 350), a multicenter, open-label, randomized (1:1), active-controlled trial. In both

trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until

disease progression or unacceptable toxicity. The trials excluded patients with abnormal left ventricular ejection

fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart

failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled

hypertension, uncontrolled arrhythmias, active brain metastases, or known history of G6PD deficiency.

Among these 559 patients, 197 (35%) were exposed to MEKINIST for > 6 months to 12 months while 185

(33%) were exposed to MEKINIST for > 1 year. The median age was 55 years (range: 18 to 91), 57% were

male, and 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance

status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline, and 0.5% had a history of brain

metastases.

The most commonly occurring adverse reactions (≥ 20%) for MEKINIST in patients receiving MEKINIST plus

dabrafenib were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.

The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are

summarized in Clinical Studies [see Clinical Studies (14.1)]. Patients receiving MEKINIST plus dabrafenib had

a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209

patients receiving MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for > 6 months to 12 months

while 46% were exposed to MEKINIST for > 1 year.

In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients

receiving MEKINIST plus dabrafenib; the most common were pyrexia (1.4%) and decreased ejection fraction

(1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients receiving

MEKINIST plus dabrafenib; the most common were pyrexia (2.9%), neutropenia (1.9%), decreased ejection

fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in

46% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (18%), chills (7%),

vomiting (6%) and decreased ejection fraction (4.8%).

Table 5 and Table 6 present selected adverse drug reactions and laboratory abnormalities, respectively, of

MEKINIST observed in the COMBI-d study.

Table 5. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving MEKINIST with

Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in the

COMBI-d Studya

Adverse Reactions

Pooled MEKINIST plus

Dabrafenib

N = 559

COMBI-d Study

MEKINIST plus

Dabrafenib N = 209

Dabrafenib

N = 211

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

General disorders and administrative site conditions

Pyrexia 54 5 57 7 33 1.9

Chills 31 0.5 31 0 17 0.5

Edema peripheralb 21 0.7 25 1.4 11 0.5

Gastrointestinal

Nausea 35 0.4 34 0.5 27 1.4

Diarrhea 31 1.3 30 1.4 16 0.9

Vomiting 27 1.1 25 1.0 14 0.5

Abdominal painc 18 0.9 26 1.0 14 2.4

Nervous system

Dizziness 11 0.2 14 0 7 0

Vascular

Hypertension 26 11 25 6 16 6

Hemorrhaged 18 2.0 19 1.9 15 1.9

Skin

Rashe 32 1.1 42 0 27 1.4 * ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients

receiving dabrafenib as a single agent a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. b Includes peripheral edema, edema, lymphedema, localized edema, and generalized edema. c Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Most common events (≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4

events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm). e Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and

folliculitis rash.

Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients receiving

MEKINIST in combination with dabrafenib (N = 559) were:

Cardiac Disorders: Bradycardia

Musculoskeletal Disorders: Rhabdomyolysis

Table 6. Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of

Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving

Single-Agent Dabrafenib in the COMBI-d Study

Test

Pooled MEKINIST

plus Dabrafenib

N = 559a

COMBI-d Study

MEKINIST plus

Dabrafenib

N = 209b

Dabrafenib

N = 211b

All

Grades

(%)

Grades

3 and 4c

(%)

All

Grades

(%)

Grades

3 and 4c

(%)

All

Grades

(%)

Grades

3 and 4c

(%)

Hematology

Neutropenia 46 7 50 6 16 1.9

Anemia 43 2.3 43 2.4 38 4.3

Lymphopenia 32 8 38 9 28 7

Thrombocytopenia 21 0.7 19 0.5 10 0.5

Liver Function Tests

Increased AST 59 4.1 60 4.3 21 1.0

Increased blood alkaline

phosphatase

49 2.7 50 1.0 25 0.5

Increased ALT 48 4.5 44 3.8 28 1.0

Chemistry

Hyperglycemia 60 4.7 65 6 57 4.3

Hypoalbuminemia 48 1.1 53 1.4 27 0

Hyponatremia 25 8 24 6 14 2.9 *≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients

receiving dabrafenib as a single agent

AST = Aspartate aminotransferase; ALT = Alanine aminotransferase. a For these laboratory tests the denominator is 556. b For these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3),

neutropenia (n = 2), and hyponatremia (n = 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT,

increased AST, hyperglycemia (each n = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased

ALT, and increased AST (each n = 1) in the dabrafenib arm.

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

The safety of MEKINIST when administered with dabrafenib was evaluated in 435 patients with Stage III

melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose

of study therapy in the COMBI-AD study [see Clinical Studies (14.2)]. Patients received MEKINIST 2 mg

orally once daily and dabrafenib 150 mg orally twice daily for 12 months. The trial excluded patients with

abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or

stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc

interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of retinal vein

occlusion. The median age of patients who received MEKINIST in combination with dabrafenib was 50 years

(range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status 0, and 8% had

baseline ECOG performance status 1. Patients receiving MEKINIST in combination with dabrafenib had a

median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients receiving

MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months.

The most commonly occurring adverse reactions (≥ 20%) in patients receiving MEKINIST in combination with

dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54%

of patients, respectively; the most common for each were pyrexia and chills. Adverse reactions leading to dose

reductions of MEKINIST occurred in 23% of patients; the most common were pyrexia and ejection fraction

decrease.

Table 7 summarizes adverse reactions that occurred in at least 20% of the patients receiving MEKINIST in

combination with dabrafenib.

Table 7. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Studya

Adverse Reactions

MEKINIST plus Dabrafenib

N = 435

Placebo

N = 432

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

General

Pyrexiab 63 5 11 < 1

Fatiguec 59 5 37 < 1

Chills 37 1 4 0

Gastrointestinal

Nausea 40 < 1 20 0

Diarrhea 33 < 1 15 < 1

Vomiting 28 < 1 10 0

Nervous system

Headached 39 1 24 0

Skin

Rashe 37 < 1 16 < 1

Musculoskeletal

Arthralgia 28 < 1 14 0

Myalgiaf 20 < 1 14 0 a NCI CTCAE version 4.0 b Includes pyrexia and hyperpyrexia c Includes fatigue, asthenia, and malaise d Includes headache and tension headache e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash,

rash vesicular, and rash pustular f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study

receiving MEKINIST in combination with dabrafenib were blurred vision (6%), ejection fraction decreased

(5%) and rhabdomyolysis (< 1%).

The most common laboratory abnormalities are summarized in Table 8.

Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in the

COMBI-AD study

Test

MEKINIST plus Dabrafeniba

N = 435

Placeboa

N = 432

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

Hematology

Neutropenia 47 6 12 < 1

Lymphopenia 26 5 6 < 1

Anemia 25 < 1 6 < 1

Liver Function Tests

Increased AST 57 6 11 < 1

Increased ALT 48 5 18 < 1

Increased blood

alkaline phosphatase

38 1 6 < 1

Chemistry

Hyperglycemia 63 3 47 2

Hypophosphatemia 42 7 10 < 1

Hypoalbuminemia 25 < 1 < 1 0 a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement:

MEKINIST plus Dabrafenib (range 429 to 431) and placebo arm (range 426 to 428)

Metastatic, BRAF V600E Mutation-Positive NSCLC

The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously

untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a

multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST

2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable

toxicity. The trial excluded patients with abnormal left ventricular ejection fraction, history of acute coronary

syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association),

QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases,

history of interstitial lung disease or pneumonitis, or history or current retinal vein occlusion [see Clinical

Studies (14.3)].

Among these 93 patients, 53 (57%) were exposed to MEKINIST and dabrafenib for > 6 months and 27 (29%)

were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 65 years (range: 41 to 91), 46%

were male, 85% were White; 32% had baseline ECOG performance status 0 and 61% had ECOG performance

status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and

28% had never smoked.

The most commonly occurring adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea,

vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of MEKINIST occurred in 19% of patients; the most common

were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%). Adverse reactions

leading to dose reductions of MEKINIST occurred in 30% of patients receiving MEKINIST plus dabrafenib;

the most common were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia

(3.2%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients receiving

MEKINIST plus dabrafenib; the most common were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea

(5%), and ejection fraction decreased (5%).

Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, of MEKINIST

in combination with dabrafenib in Study BRF113928.

Table 9. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with MEKINIST plus

Dabrafenib in Study BRF113928a

Adverse Reactions


N = 93

All

Grades

(%)

Grades

3 and 4b

(%)

General

Pyrexia 55 5

Fatigueb 51 5

Edemac 28 0

Chills 23 1.1

Gastrointestinal

Nausea 45 0

Vomiting 33 3.2

Diarrhea 32 2.2

Decreased appetite 29 0

Respiratory system

Cough 22 0

Dyspnea 20 5

Skin

Dry skin 31 1.1

Rashd 28 3.2

Vascular

Hemorrhagee 23 3.2 a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder

hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients

Receiving MEKINIST plus Dabrafenib in Study BRF113928

Test


N = 93

All

Grades

(%)

Grades

3 and 4

(%)

Hematologya

Leukopenia 48 8

Anemia 46 10

Neutropenia 44 8

Lymphopenia 42 14

Liver Function Testsb

Increased blood alkaline phosphatase 64 0

Increased AST 61 4.4

Increased ALT 32 6

Chemistryb

Hyperglycemia 71 9

Hyponatremia 57 17

Hypophosphatemia 36 7

Increased creatinine 21 1.1 a For these laboratory tests the denominator is 91. b For these laboratory tests the denominator is 90.

Locally Advanced or Metastatic, BRAF V600E-Mutation Positive, Anaplastic Thyroid Cancer (ATC)

The safety of MEKINIST when administered with dabrafenib was evaluated in a nine-cohort, multicenter, non-

randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally

advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, a total of 100 patients were

enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all

patients who received at least one dose of MEKINIST or dabrafenib. Patients received MEKINIST 2 mg orally

once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity.

Among these 100 patients, 46 (46%) were exposed to MEKINIST and dabrafenib for > 6 months and 23 (23%)

were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 59.5 years (range: 18 to 85);

62% were male; 85% were White; and 31% had baseline ECOG performance status 0 and 59% had ECOG

performance status 1.

The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that

observed in other approved indications.

7 DRUG INTERACTIONS

No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated

drug interactions with trametinib [see Clinical Pharmacology (12.3)].

MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib labeling for additional

risk information that applies to combination use treatment.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal

harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There is insufficient data in

pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in

rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human

exposure at the recommended clinical dose (see Data). If MEKINIST is used during pregnancy, or if the patient

becomes pregnant while taking MEKINIST, advise the patient of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of

organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day

(approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose

resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal

toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal

body weight and increased incidence of variations in ossification at doses greater than or equal to

0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In

rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the

recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of

pregnancy, compared with control animals.

8.2 Lactation

Risk Summary

There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed

infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from

MEKINIST, advise women not to breastfeed during treatment with MEKINIST and for 4 months following the

last dose.

8.3 Females and Males of Reproductive Potential

Contraception

Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal

harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Females: Advise female patients of reproductive potential to use effective contraception during treatment with

MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they

become pregnant, or if pregnancy is suspected, while taking MEKINIST.

Infertility

Females: Advise female patients of reproductive potential that MEKINIST may impair fertility. Increased

follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3

times the human exposure at the recommended dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been

established in pediatric patients.

Juvenile Animal Data

In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at

doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on

AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times

the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric Use

Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older

to determine whether they respond differently from younger subjects.

Of the 994 patients with melanoma randomized to receive MEKINIST plus dabrafenib in the COMBI-d,

COMBI-v, and COMBI-AD studies, 21% were aged 65 years and older and 5% were aged 75 years and older.

No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in elderly patients as

compared to younger patients across the melanoma studies. The incidences of peripheral edema (26% vs. 12%)

and anorexia (21% vs. 9%) increased in elderly patients as compared to younger patients in the metastatic

melanoma studies.

Clinical studies of MEKINIST in NSCLC did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

No dose adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology

(12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe

hepatic impairment.

8.7 Renal Impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment [see Clinical

Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with severe

renal impairment.

10 OVERDOSAGE

The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg

administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on

one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of

28%.

Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of

overdose with MEKINIST.

11 DESCRIPTION

Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-

[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-

yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C26H23FIN5O4C2H6OS

with a molecular mass of 693.53. Trametinib dimethyl sulfoxide has the following chemical structure:

Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2

to 8 in aqueous media.

MEKINIST (trametinib) tablets for oral use are supplied as 0.5 mg and 2 mg tablets for oral administration.

Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-

solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of

trametinib non-solvated parent.

The inactive ingredients of MEKINIST tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose

sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium

lauryl sulfate. Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets),

polyethylene glycol, polysorbate 80 (2 mg tablets), titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and

MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the

extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E

mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib

inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.

Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib

and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell

lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts

compared with either drug alone.

12.2 Pharmacodynamics

Administration of 1 mg and 2 mg MEKINIST to patients with BRAF V600 mutation-positive melanoma

resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition

of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis).

Cardiac Electrophysiology

The heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in a dedicated study in 32

patients who received placebo on day 1 and MEKINIST 2 mg once daily on days 2-14 followed by MEKINIST

3 mg on day 15. No clinically relevant QTc prolongation was detected in the study.

In clinical trials in patients receiving MEKINIST in combination with dabrafenib, QTc prolongation > 500 ms

occurred in 0.8% of patients, and QTc increased by > 60 ms from baseline in 3.8% of patients.

12.3 Pharmacokinetics

The pharmacokinetics of trametinib were characterized following single- and repeat-oral administration in

patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.

Absorption

After oral administration of MEKINIST, the median time to achieve peak plasma concentrations (Tmax) is

1.5 hours post-dose. The mean absolute bioavailability of a single oral dose of MEKINIST 2 mg is 72%. The

increase in Cmax was dose proportional after a single dose of 0.125 mg (0.0625 times the approved

recommended dosage) to 10 mg (5 times the approved recommended dosage) while the increase in AUC was

greater than dose proportional. After repeat doses of 0.125 mg to 4 mg daily, both Cmax and AUC increase

proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%,

respectively.

Effect of Food

Administration of a single dose of MEKINIST with a high-fat, high-calorie meal (approximately 1000 calories)

decreased trametinib AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with

fasted conditions.

Distribution

Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.

Elimination

The estimated elimination half-life of trametinib based on the population PK model is 3.9 to 4.8 days. The

apparent clearance is 4.9 L/h.

Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination

with glucuronidation biotransformation pathways in vitro. Deacetylation is mediated by carboxylesterases (i.e.,

carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes.

Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the

parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥ 75% of drug-

related material in plasma is the parent compound.

Excretion

Following oral administration of [14C]-trametinib, greater than 80% of excreted radioactivity was recovered in

the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the

excreted dose as parent.

Specific Populations

Age, Body Weight, and Sex: Age, sex, and body weight do not have a clinically important effect on the exposure

of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race

or ethnicity.

Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic

impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin greater than 1 to 1.5 x ULN and any AST),

mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The

pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment.

Renal Impairment: Based on a population pharmacokinetic analysis in 223 patients with mild renal impairment

(GFR 60 to 89 mL/min/1.73 m2) and 35 patients with moderate renal impairment (GFR 30 to

59 mL/min/1.73 m2), mild and moderate renal impairment have no clinically important effects on the systemic

exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with severe renal

impairment.

Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients.

Drug Interactions

Effect of Trametinib on CYP Substrates: Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is

not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at a clinically

relevant systemic concentration of 0.04 µM. Trametinib is an inducer of CYP3A in vitro. Based on cross-study

comparisons, oral administration of MEKINIST 2 mg once daily with a sensitive CYP3A4 substrate had no

clinically important effect on the AUC and Cmax of the sensitive CYP3A4 substrate.

Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and bile salt extrusion

pump (BSEP). Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib

concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate

of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP1B1, OATP1B3,

OATP2B1), organic cation transporter 1 (OCT1), multidrug resistance protein 2 (MRP2), or multidrug and

toxin extrusion 1 (MATE1) in vitro.

Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP,

OATP1B1, OATP1B3, organic anion transporter (OAT1, OAT3), OCT2, BSEP, MRP2, or MATE1 at a

clinically relevant systemic concentration of 0.04 µM.

Effect of Dabrafenib on Trametinib: Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice

daily resulted in no change in AUC of trametinib as compared with administration of trametinib.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies

evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the

bone marrow of rats.

Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased

follicular cysts and decreased corpora lutea were observed at doses ≥ 0.016 mg/kg/day (approximately 0.3 times

the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in

duration, there were no treatment effects observed on male reproductive tissues [see Use in Specific Populations

(8.3)].

14 CLINICAL STUDIES

14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

MEKINIST as a Single Agent

The safety and efficacy of MEKINIST were evaluated in an international, multicenter, randomized (2:1), open-

label, active-controlled trial (the METRIC study; NCT01245062) in 322 patients with BRAF V600E or V600K

mutation-positive, unresectable or metastatic melanoma.

In the METRIC study, patients were not permitted to have more than one prior chemotherapy regimen for

advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The

primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive

MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine

1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment

continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior

use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level

(normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central

testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST

and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion

diagnostic test, THxID™-BRAF assay.

The median age for randomized patients was 54 years, 54% were male, greater than 99% were White, and all

patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were

Stage M1c (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior

chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF

V600E (87%), V600K (12%), or both (less than 1%). The median durations of follow-up prior to initiation of

alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated

with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease

progression to receive MEKINIST.

The METRIC study demonstrated a statistically significant increase in progression-free survival in the patients

treated with MEKINIST. Table 11 and Figure 1 summarize the PFS results.

Table 11. Investigator-Assessed Progression-Free Survival and Confirmed Objective Response Results in

the METRIC Study

Investigator-Assessed Endpoints† MEKINIST

N = 214

Chemotherapy

N = 108

Progression-Free Survival

Number of Events (%) 117 (55%) 77 (71%)

Progressive Disease 107 (50%) 70 (65%)

Death 10 (5%) 7 (6%)

Median, months (95% CI) 4.8 (4.3, 4.9) 1.5 (1.4, 2.7)

HRa (95% CI) 0.47 (0.34, 0.65)

P value (log-rank test) < 0.0001

Confirmed Tumor Responses

Objective Response Rate 22% 8%

(95% CI) (17, 28) (4, 15)

CR, n (%) 4 (2%) 0

PR, n (%) 43 (20%) 9 (8%)

Duration of Response

Median, months (95% CI) 5.5 (4.1, 5.9) NR (3.5, NR) † CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. a Pike estimator.

Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in

the METRIC Study

In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results

were consistent with those of the primary efficacy analysis.

MEKINIST with Dabrafenib

The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international,

randomized, double-blind, active-controlled trial (the COMBI-d study; NCT01584648). The COMBI-d study

compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with

unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous

melanoma. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg

twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by lactate

dehydrogenase (LDH) level (greater than the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation

subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival

(PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed

overall response rate (ORR).

In the COMBI-d study, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib

plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, > 99% were

White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal

LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or

V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85%

had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma.

The COMBI-d study demonstrated statistically significant improvements in PFS and OS (see Table 12 and

Figure 2).

Table 12. Efficacy Results in the COMBI-d Study

Endpoint†

MEKINIST plus

Dabrafenib

N = 211

Dabrafenib

plus Placebo

N = 212

Progression-Free Survival (PFS)a

Number of events (%) 102 (48%) 109 (51%)

Median, months

(95% CI)

9.3

(7.7, 11.1)

8.8

(5.9, 10.9)

HR (95% CI) 0.75 (0.57, 0.99)

P valueb 0.035

Overall Survival

Number of deaths (%) 99 (47% ) 123 (58%)

Median, months

(95% CI)

25.1

(19.2, NR)

18.7

(15.2, 23.1)

HR (95% CI) 0.71 (0.55, 0.92)

P valueb 0.01

Overall Response Rate (ORR)a

ORR, %

(95% CI) 66 (60, 73) 51 (44, 58)

P value < 0.001

CR, % 10 8

PR, % 56 42

Median duration of

response, months (95% CI) 9.2 (7.4, NR) 10.2 (7.5, NR)

† CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. a PFS and ORR were assessed by investigator. b Based on stratified log-rank test.

Figure 2. Kaplan Meier Curves of Overall Survival in the COMBI-d Study

14.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

COMBI-AD (NCT01682083) was an international, multi-center, randomized, double-blind, placebo-controlled

trial that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the

THxID™-BRAF assay and pathologic involvement of regional lymph node(s). Patients were randomized (1:1)

to receive MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for

up to 1 year. Enrollment required complete resection of melanoma with complete lymphadenectomy within 12

weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-

transit metastases, distant metastatic disease, or prior systemic anticancer treatment, including radiotherapy.

Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on

Cancer (AJCC; 7th Edition) stage (IIIa, IIIb, or IIIc). The major efficacy outcome measure was relapse-free

survival (RFS) defined as the time from randomization to disease recurrence (local, regional, or distant

metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the

investigator. Patients underwent imaging for tumor recurrence every 3 months for the first two years and every

6 months thereafter.

In COMBI-AD, a total of 870 patients were randomized: 438 to the MEKINIST in combination with dabrafenib

and 432 to placebo. Median age was 51 years (range: 18 to 89), 55% were male, 99% were White, and 91% had

an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIa (18%), Stage IIIb (41%), Stage

IIIc (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic

lymph nodes (65%); and tumor ulceration (41%). The median duration of follow-up (time from randomization

to last contact or death) was 2.8 years.

COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in

combination with dabrafenib arm compared to those randomized to placebo. Efficacy results are presented in

Table 13 and Figure 3.

Table 13. Efficacy Results in COMBI-AD in the Adjuvant Treatment of Melanoma


N = 438

Placebo

N = 432

Relapse-Free Survival (RFS)

Number of events (%)

Median in months (95% CIa)

166 (38)

NEb (44.5, NEb)

248 (57)

16.6 (12.7, 22.1)

Hazard ratio (95% CI)c

P valued

0.47 (0.39, 0.58)

< 0.0001

a CI = Confidence interval b NE = Not estimable c Pike estimator obtained from the stratified log-rank test d Log-rank test stratified by disease stage – IIIA vs. IIIB vs. IIIC – and BRAF V600 mutation type – V600E vs. V600K)

Figure 3. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of

Melanoma

14.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

In Study BRF113928 (NCT01336634), the safety and efficacy of dabrafenib alone or administered with

MEKINIST were evaluated in a multicenter, three-cohort, non-randomized, activity-estimating, open-label trial.

Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior

exposure to BRAF or MEK inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients

had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts A and B were required

to have received at least one previous platinum-based chemotherapy regimen with demonstrated disease

progression but no more than three prior systemic regimens. Patients in Cohort C could not have received prior

systemic therapy for metastatic disease. Patients in Cohort A received dabrafenib 150 mg twice daily. Patients

in Cohorts B and C received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major

efficacy outcome was overall response rate (ORR) per RECIST v1.1 as assessed by independent review

committee (IRC) and duration of response.

There were a total of 171 patients enrolled, which included 78 patients enrolled in Cohort A, 57 patients

enrolled in Cohort B, and 36 patients enrolled in Cohort C. The characteristics of the population were: a median

age of 66 years; 48% male; 81% White, 14% Asian, 3% Black and 2% Hispanic; 60% former smokers, 32%

never smokers, and 8% current smokers; 27% had ECOG performance status (PS) of 0, 63% had ECOG PS of

1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and

14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting, 58% of the

135 previously treated patients had only one line of prior systemic therapy for metastatic disease; 98% had non-

squamous histology.

Efficacy results are summarized in Table 14.

Table 14. Efficacy Results Based on Independent Review in Study BRF113928

Treatment Dabrafenib Dabrafenib + Trametinib

Population

Previously Treated

n = 78 Previously Treated

n = 57 Treatment Naïve

n = 36

Overall Response Rate (95% CI)a 27% (18%, 38%) 63% (49%, 76%) 61% (44%, 77%)

Complete response 1% 4% 3%

Partial response 26% 60% 58%

Duration of Response (DOR) = 21 = 36 = 22

Median DOR, months (95% CI)a 9.9 (4.2, NEb) 12.6 (5.8, NE) NE (6.9, NE)

% Responders with DOR ≥ 6 months 52% 64% 59%

aConfidence interval bNot estimable

In a subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive

NSCLC with the Oncomine™ Dx Target Test, the ORR results were similar to those presented in Table 14.

14.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer

(ATC)

The safety and efficacy of MEKINIST administered with dabrafenib was evaluated in Study BRF117019

(NCT02034110), an activity-estimating, nine-cohort, multi-center, non-randomized, open-label trial in patients

with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic

anaplastic thyroid cancer (ATC) with no standard locoregional treatment options. Trial BRF117019 excluded

patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK

inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction.

Patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome

measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC)

and duration of response (DoR).

At the time of efficacy analysis, 23 patients were evaluable for response in the ATC cohort. Three additional

patients were enrolled; however, there was insufficient time to assess response of these patients. Among the 26

patients enrolled, the median age was 70 years (range 49-85); 50% were male, 50% White, 46% Asian; 100%

had ECOG performance status of 0 or 1; and 54% had a prior history of differentiated thyroid cancer. Prior

anti-cancer treatments included surgery (92%), external beam radiotherapy (81%), and systemic therapy (54%).

Efficacy results are summarized in Table 15.

Table 15. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019

ATC Cohort Population (evaluable for response) n = 23

Objective Response Rate (ORR)

ORR (95%CI)a 61% (39%, 80%)

Complete Response Rate 4%

Partial Response Rate 57%

Duration of Response (DOR)

% with DOR ≥6 months 64% aCI = Confidence interval b NE=Not estimable

14.5 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy

The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multicenter, international

trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who

had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally

once daily until disease progression or unacceptable toxicity.

The median age was 58 years, 63% were male, all were White, 98% had baseline ECOG PS of 0 or 1, and the

distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had

multiple V600 mutations (5%), or unknown mutational status (2%). No patient achieved a confirmed partial or

complete response as determined by the clinical investigators.

16 HOW SUPPLIED/STORAGE AND HANDLING

0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’

on the opposing face and are available in bottles of 30 (NDC 0078-0666-15).

2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the

opposing face and are available in bottles of 30 (NDC 0078-0668-15).

Store refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in original bottle. Do not remove desiccant. Protect

from moisture and light. Do not place medication in pill boxes.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the following:

Confirmation of BRAF V600E or V600K mutation

Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary to identify patients for

whom treatment with MEKINIST is indicated [see Dosage and Administration (2.1)].

New cutaneous and non-cutaneous malignancies

MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-

cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to

existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions

(5.1)].

Hemorrhage

MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage.

Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms

of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)].

Colitis and gastrointestinal perforation

MEKINIST can cause colitis and gastrointestinal perforation. Advise patients to contact their healthcare

provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)].

Venous thrombosis

MEKINIST administered with dabrafenib increases the risks of pulmonary embolism and deep venous

thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg

pain, or swelling [see Warnings and Precautions (5.4)].

Cardiomyopathy

MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart

failure to their healthcare provider [see Warnings and Precautions (5.5)].

Retinal Pigment Epithelial Detachment

MEKINIST can cause severe visual disturbances that can lead to blindness. Advise patients to contact their

healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

Interstitial lung disease

MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare

provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions

(5.7)].

Serious febrile reactions

MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their

healthcare provider if they develop fever while taking MEKINIST with dabrafenib [see Warnings and

Precautions (5.8)].

Serious skin toxicities

MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their

healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.9)].

Hypertension

MEKINIST can cause hypertension. Advise patients that they need to undergo blood pressure monitoring and to

contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry

vision, or dizziness.

Diarrhea

MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact

their healthcare provider if severe diarrhea occurs during treatment.

Embryo-fetal Toxicity

MEKINIST can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a

fetus [see Warnings and Precautions (5.12), Use in Specific Populations (8.1, 8.3)].

Females and males of reproductive potential

Instruct females of reproductive potential to use highly effective contraception during treatment with

MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they

become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Warnings and Precautions (5.12),

Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use

in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific

Populations (8.3)].

Instructions for taking MEKINIST

MEKINIST should be taken at least 1 hour before or at least 2 hours after a meal [see Dosage and


THxID BRAF™ assay is a trademark of bioMérieux.

Oncomine™ Dx Target Test is a trademark of Life Technologies Corporation, a part of Thermo Fisher

Scientific Inc.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

T2018-68

Patient Information

MEKINIST® (MEK-in-ist)

(trametinib)

tablets

Important information: If your healthcare provider prescribes MEKINIST for you to be taken with dabrafenib, also read the Medication Guide that comes with dabrafenib.

What is the most important information I should know about MEKINIST?

MEKINIST may cause serious side effects, including:

Risk of new skin cancers. MEKINIST, when used with dabrafenib, may cause skin cancers, called cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, or melanoma.

Talk to your healthcare provider about your risk for these cancers.

Check your skin and tell your healthcare provider right away about any skin changes including a:

new wart

skin sore or reddish bump that bleeds or does not heal

change in size or color of a mole

Your healthcare provider should check your skin before treatment with MEKINIST and dabrafenib, every 2 months during treatment with MEKINIST and dabrafenib and for up to 6 months after you stop taking MEKINIST and dabrafenib to look for any new skin cancers.

Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with MEKINIST with dabrafenib.

See "What are the possible side effects of MEKINIST?" for more information about side effects.

What is MEKINIST?

MEKINIST is a prescription medicine used:

alone or in combination with a medicine called dabrafenib to treat a type of skin cancer called melanoma: o that has spread to other parts of the body or cannot be removed by surgery, and o that has a certain type of abnormal “BRAF” gene.

in combination with dabrafenib, to help prevent melanoma that has a certain type of abnormal “BRAF” gene from coming back after the cancer has been removed by surgery.

MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma, and it did not work or is no longer working.

in combination with dabrafenib to treat a type of lung cancer called non-small cell lung cancer (NSCLC) o that has spread to other parts of the body, and

o that has a certain type of abnormal “BRAF” gene.

in combination with dabrafenib to treat a type of thyroid cancer called anaplastic thyroid cancer (ATC) o that has spread to other parts of the body and you have no satisfactory treatment options, and

o that has a certain type of abnormal “BRAF” gene

Your healthcare provider will perform a test to make sure that MEKINIST is right for you.

It is not known if MEKINIST alone or MEKINIST with dabrafenib is safe and effective in children.

Before you take MEKINIST, tell your healthcare provider about all of your medical conditions, including if you:

have had bleeding problems or blood clots

have stomach problems

have inflammation of the colon

have heart problems

have eye problems

have lung or breathing problems

have high blood pressure (hypertension)

have liver or kidney problems

have diabetes

are pregnant or plan to become pregnant. MEKINIST can harm your unborn baby.

o Females who are able to become pregnant should use effective birth control (contraception) during treatment with MEKINIST and for 4 months after your last dose of MEKINIST.

o Talk to your healthcare provider about birth control methods that may be right for you during this time.

o Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with MEKINIST.

are breastfeeding or plan to breastfeed. It is not known if MEKINIST passes into your breast milk.

o Do not breastfeed during treatment and for 4 months after your last dose of MEKINIST. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take MEKINIST?

Take MEKINIST exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST unless your healthcare provider tells you.

Your healthcare provider may change your dose of MEKINIST, temporarily stop, or completely stop your treatment with MEKINIST if you develop certain side effects.

Take MEKINIST one time a day, about every 24 hours.

Take MEKINIST at least 1 hour before or 2 hours after a meal.

If you miss a dose, take it as soon as you remember. If it is less than 12 hours before your next scheduled dose, skip the missed dose. Just take the next dose at your regular time.

What are the possible side effects of MEKINIST?

MEKINIST may cause serious side effects, including:

See “What is the most important information I should know about MEKINIST?”

bleeding problems. MEKINIST can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including:

o headaches, dizziness, or feeling weak

o cough up blood or blood clots

o vomit blood or your vomit looks like “coffee grounds”

o red or black stools that look like tar

inflammation of the intestines, or tears (perforation) of the stomach or intestines. MEKINIST can cause inflammation of your intestines, or tears in the stomach or intestines that can lead to death. Tell your healthcare provider immediately if you have any of the following symptoms:

o bleeding. see “bleeding problems” above

o diarrhea (loose stools) or more bowel movements than usual

o stomach-area (abdomen) pain or tenderness

o fever

o nausea

blood clots. MEKINIST can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms:

o chest pain

o sudden shortness of breath or trouble breathing

o pain in your legs with or without swelling

o swelling in your arms or legs

o a cool pale arm or leg

heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with MEKINIST. Call your healthcare provider right away if you have any of the following signs and symptoms of a heart problem:

o feeling like your heart is pounding or racing

o shortness of breath

o swelling of your ankles and feet

o feeling lightheaded

eye problems. MEKINIST can cause severe eye problems that might lead to blindness. Call your healthcare provider right away if you get these symptoms of eye problems:

o blurred vision, loss of vision, or other vision changes

o see color dots

o halo (seeing blurred outline around objects)

o eye pain, swelling, or redness

lung or breathing problems. MEKINIST can cause lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including:

o shortness of breath

o cough

fever. Fever is common during treatment with MEKINIST and dabrafenib, but it may also be serious. When taking MEKINIST with dabrafenib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Call your healthcare provider right away if you get a fever during treatment with MEKINIST.

serious skin reactions. Rash is a common side effect of MEKINIST. MEKINIST can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe or serious, and may need to be treated in a hospital. Call your healthcare provider if you get any of the following symptoms:

o skin rash that bothers you or does not go away

o acne

o redness, swelling, peeling, or tenderness of hands or feet

o skin redness

increased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with MEKINIST and dabrafenib. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with MEKINIST and dabrafenib. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar:

o increased thirst

o urinating more often than normal or urinating an increased amount of urine

The most common side effects of MEKINIST when taken alone include:

rash

diarrhea. Call your healthcare provider if you get severe diarrhea.

swelling of the face, arms, or legs

The most common side effects of MEKINIST when taken with dabrafenib in people with melanoma that has spread to other parts of the body or cannot be removed by surgery include:

fever diarrhea

rash vomiting

nausea high blood pressure (hypertension)

chills swelling of the face, arms, or legs

The most common side effects of MEKINIST when taken with dabrafenib to help prevent melanoma from coming back after the cancer has been removed by surgery include:

fever

fatigue

nausea

headache

rash

chills

diarrhea

vomiting

joint aches

muscle aches

The most common side effects of MEKINIST when taken with dabrafenib in people with NSCLC include:

fever

fatigue

nausea

vomiting

rash

swelling of face, arms, and legs

chills

bleeding

diarrhea

dry skin

decreased appetite

cough

shortness of breath

MEKINIST can cause new or worsening high blood pressure (hypertension). Your healthcare provider should check your blood pressure during treatment with MEKINIST. Call your healthcare provider right away if you develop high blood pressure, your blood pressure worsens, or you have severe headache, lightheadedness, blurry vision, or dizziness.

MEKINIST may cause fertility problems in females. This could affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of MEKINIST.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Novartis Pharmaceuticals Corporation at 1-888-669-6682.

How should I store MEKINIST?

Store MEKINIST in the refrigerator between 36°F to 46°F (2°C to 8°C).

Keep MEKINIST dry and away from moisture and light.

The bottle of MEKINIST contains a desiccant packet to help keep your medicine dry. Do not throw away the desiccant packet.

Keep MEKINIST in its original bottle. Do not place tablets in a pill box.

Safely throw away MEKINIST that is out of date or no longer needed.

Keep MEKINIST and all medicine out of the reach of children.

General information about the safe and effective use of MEKINIST.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MEKINIST for a condition for which it was not prescribed. Do not give MEKINIST to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about MEKINIST that is written for health professionals.

What are the ingredients in MEKINIST?

Active ingredient: trametinib

Inactive ingredients:

Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate.

Tablet Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), titanium dioxide. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 For more information, go to www.MEKINIST.com or call 1-888-669-6682.

© Novartis

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: May 2018

T2018-69

http://www.mekinist.com/

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